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研究生:易麗娜
研究生(外文):Li-na Yi
論文名稱:Manganese superoxide Dismutase (SOD2)過度表現對抑制肝癌細胞致癌性的研究
論文名稱(外文):Overexpression of Manganese Superoxide Dismutase (SOD2) Inhibited the Tumorigenicity of Hepatoma Cells
指導教授:戴明泓
指導教授(外文):Ming-Hong Tai
學位類別:碩士
校院名稱:國立中山大學
系所名稱:生物科學系研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:英文
論文頁數:61
中文關鍵詞:活性氧化物肝細胞癌超氧陰離子過氧化氫錳超氧化物歧化酶
外文關鍵詞:Hydrogen peroxidereactive oxygen speciesMn superoxide dismutaseHepatocellular carcinomasuperoxide anions
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在台灣肝細胞癌是最常見的一種惡性腫瘤。 肝臟細胞癌化,會由於氧化壓力間的活性氧化物(ROS)和解毒作用不平衡而發生。當細胞受到自由基破壞時,超氧化物歧化酶(SODS)發揮關鍵性的解毒作用,保護細胞來至自由基導致的損傷。錳超氧化物歧化酶(MnSOD或SOD2)是超氧化物歧化酶(SODS)成員之ㄧ存在於線粒體內。SOD2生理作用是將線粒體內具毒性的超氧陰離子( O2- )轉變成過氧化氫( H2O2 )。在人類肝癌組織樣本中已經證實SOD2表現量減弱,而SOD2表現減弱與肝癌細胞形成的關聯性目前仍然不清楚。在本論文中,首先證明在人類惡性肝癌細胞株SK-Hep-1細胞中SOD2 的表現量較良性肝癌細胞株少。此外, 在141例手術切除之肝癌樣本中,其中97例( 68.8 % ) SOD2的表現明顯低於鄰近非腫瘤組織。運用腺病毒傳送SOD2基因在SK-Hep-1肝癌細胞中,會增加SOD2蛋白表現量和過氧化氫(H2O2)產量, 然而會減少超氧陰離子( O2- )含量。而且,在SOD2基因傳送明顯著抑制SK-Hep-1細胞的增殖,轉移和菌落生長。在體內動物實驗中, SOD2的過度表現會抑制腫瘤的生長且SOD2的增加能有效的抑制腫瘤細胞生長的速度及大小。在流式細胞儀實驗分析顯示,SOD2基因傳送誘導抑制肝癌細胞之細胞週期停滯在G2/M期,經由減少cdc2/cdk1和 cyclin B1的表現,及增加p21Cip1的生成有相互關聯性。然而,SOD2過度表現不影響matrix metalloproteinase-2 (MMP-2) and MMP-9的分泌。結論,本論文證明SOD2過度表達可抑制肝癌細胞的致癌性發生,有可能運用於肝癌治療。
Hepatocellular carcinoma (HCC) is one of the most common and devastating malignant tumors in Taiwan. Due to an imbalanced between reactive oxygen species (ROS) production and detoxification, oxidative stress, has been implicated in liver carcinogenesis. Superoxide dismutases (SODS) play a key role in the detoxification of superoxide radicals and thus protect cells from damage induced by free radicals. Manganese superoxide dismutase (MnSOD or SOD2) is a member of the superoxide dismutase family located in mitochondria. SOD2 transforms toxic superoxide, a byproduct of the mitochondrial electron transport chain, into hydrogen peroxide and diatomic oxygen. Though reduced SOD2 protein level and activities have been reported in hepatoma tissues, it remains unclear how SOD2 expression affected the tumorigenic processes of hepatoma cells. Expression analysis of an array of human HCC cell lines revealed that SOD2 were down-regulated in poorly differentiated SK-Hep-1 hepatoma cells. Moreover, SOD2 is downregulated in 68.8% of resected HCC samples (97 out of 141 cases). Adenovirus-mediated SOD2 gene delivery increased the cellular SOD2 protein level and H2O2 production, but reduced the superoxide anion level in SK-Hep-1 cells. Furthermore, SOD2 restoration significantly reduced the proliferation, motility, and colony formation of SK-Hep-1 cells. In vivo animal model, the finding of SOD2 overexpression inhibited the proliferation of Sk-Hep-1 hepatoma cells while reduced the tumor growth in mice. Flow cytometry analysis showed that SOD2 gene transfer inhibited the growth of hepatoma cells through induction of cell cycle arrest at G2/M phase. This was associated with declined cdc2/cdk1 and cyclin B1 expression and upregulation p21Cip1 by SOD2 gene delivery. However, SOD2 overexpression had no effect on the secretion of matrix metalloproteinase-2 (MMP-2) and MMP-9.In conclusion, SOD2 overexpression suppresses the tumorigenicity of hepatoma cells and may hold promise for HCC treatment.
CONTENTS
Page
Approval letter ........................................................... ii
Abstract in Chinese................................................... iii
Abstract in English…………………………………. iv
Abbreviation……………………………………….... vii
Introduction ....……………………………………… 1
Specific Aims ...…………………………………….. 8
Materials and Methods ...…………………………. 9
Results ....................................................................... 18
Discussion ............................................................... 25
Figures and Legends .............................................. 29
Table I ........................................................................ 46
Table II ....................................................................... 47
Appenedix ................................................................. 48
References................................................................. 49
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